Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/205—Amine addition salts of organic acids; Inner quaternary ammonium salts, e.g. betaine, carnitine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
  • A61P13/12—Drugs for disorders of the urinary system of the kidneys

Definitions

• the present invention relates to a composition suitable for the prevention and treatment of kidney dysfunctions and diseases.
• the composition may take the form and exert the activity of a food supplement or of an actual medicinal drug, depending upon the support or preventive action or the strictly therapeutic action which the composition is intended to exert according to the particular individuals for whom it is to be used.
• composition according to the present invention is suitable for the prevention and treatment of all forms of nephropathy, whether caused by external agents such as nephrotoxic drugs like lithium, antibiotics and anticancer drugs with a nephrotoxic potential, environmental contaminants such as mycotoxins of the ochratoxin type, or due to kidney function deficits of metabolic origin.
• composition according to the present invention comprises as its characterising ingredients acetyl L-carnitine and propionyl L-carnitine or the pharmacologically acceptable salts thereof which will be identified hereinbelow.
• carnitines in the field of nephrology (where the term “carnitines” refers collectively to both L-carnitine and to the lower alkanoyl L-carnitines such as acetyl, propionyl, butyryl L-carnitine, etc.) is already known.
• U.S. Pat. Nos. 4,272,549 and 4,287,167 (Sigma-Tau Industrie Farmaceutiche Riunite S.p.A.) describe the use of L-carnitine and of the above-mentioned respective alkanoyl L-carnitines to prepare polysaline solutions which are fed into the dialysis compartment of artificial kidneys.
• the purpose of the presence of said carnitines in the dialysis fluid is to counteract the loss of L-carnitine in the blood and tissues which habitually occurs in patients undergoing regular haemodialysis treatment, with the consequent onset of disorders of the skeletal muscle and myocardium.
• L-carnitine may be the cause of tubular necrosis following kidney transplantation.
• EP 0722 724 discloses the use of L-carnitine or lower alkonyl L-carnitine for preparing a medicament apt to inhibit nephro- and vasculotoxicity induced by the administration of immunosuppressants such as cyclosporin-A, tacrolimus, rapamicine and deoxyspargualine; and Drugs Exptl. Clin Res. XXI (6), 221-228 (1995) specifically reports on the protective effect of propionyl L-carnitine on cyclosporine-induced nephrotoxicity.
• composition according to the present invention consisting of a combination of acetyl L-carnitine and propionyl L-carnitine or the pharmacologically acceptable salts thereof presents a potent kidney-protecting action, particularly as regards the prevention and treatment of kidney function impairments caused by toxic agents or metabolism disorders.
• the w/w ratio of acetyl L-carnitine to propionyl L-carnitine ranges from 1:1 to 1:10.
• composition may also contain an additional carnitine selected from the group consisting of L-carnitine, butyryl L-carnitine, valeryl L-canitine and isovaleryl L-carnitine or their pharmacologically acceptable salts.
• an additional carnitine selected from the group consisting of L-carnitine, butyryl L-carnitine, valeryl L-canitine and isovaleryl L-carnitine or their pharmacologically acceptable salts.
• the w/w ratio of acetyl L-carnitine and propionyl L-carnitine to this additional carnitine ranges from 1:0.5 to 1:2.
• Additional optional components comprise vitamins, coenzymes, minerals and antioxidants.
• kidney-protecting activity exerted by the combination of acetyl L-carnitine and propionyl L-carnitine is shown by the results of a number of experimental tests which are reported here below.
• Intraperitoneal administration was done for the same period of time with 50 mg/kg or 250 mg/kg of acetyl L-carnitine or with 50 mg/kg or 250 mg/kg of propionyl L-carnitine or with the same doses of the two drugs in combination. Twenty-four hours after injection, blood samples were taken from the animals thus treated as well as from the control animals. On the plasma obtained by centrifuging, creatinine was determined according to the Taussky method (Taussky H. H., Clin. Chem. Acta, 1, 20, 1956), plasma proteins according to the Lowry method (Lowry O. H., Rosembrough N. J., Fan A. L., Randall R. Y., J. Biol. Chem., 193, 265, 1951) and urea by means of reaction with diacetyl monoxime.
• the glycerol-induced acute renal insufficiency was demonstrated by a substantial increase in plasma concentrations of both urea and creatinine.
• acetyl L-carnitine or propionyl L-carnitine alone produced only slight changes in the elevated plasma urea and creatinine concentrations, whereas a surprisingly marked reduction was noted when acetyl L-carnitine and propionyl L-carnitine were administered in combination.
• tubulo-interstitial nephropathy similar to that encountered in man and known as Balkans Endemic Nephropathy (BEN) by means of the administration of a mycotoxin produced by Aspergillus ochraceus which is present as a contaminant in various foodstuffs and is known as ochratoxin A (Kniper-Goodman T., Scott P., Biomed. Environ. Sci., 2, 179, 1989).
• this toxin causes a series of renal abnormalities in the rat with a reduction in glomerular filtration and lesions at the level of the proximal tubule to such an extent as to cause renal atrophy.
• a panel of tests conducted in rats intoxicated with ochratoxin A it proved possible to demonstrate that, in this experimental model, too, the administration of the combination of acetyl L-carnitine and propionyl L-carnitine exerts an important protective effect against the renal abnormalities induced by the toxin. This effect is surprisingly greater than would be expected on summing the single effects obtained with the use of acetyl L-carnitine alone or propionyl L-carnitine alone.
• a batch of Wistar rats with a mean body weight of 200 g was divided into various groups, one of which served as a control group, while another was administered 300 mg/kg of ochratoxin (Sigma Chemical, St. Louis, Mo. USA) by gastric probe every 48 hours for a period of ten days.
• the remaining groups in addition to ochratoxin, also received oral administrations of 300 mg/kg of acetyl L-carnitine or 800 mg/kg of propionyl L-cacnitine or a combination of the two carnitines for the entire 10-day treatment period.
• ALP alkaline phosphatase
• GTT gamma-glutamyl transferase
• NAG N-acetyl- ⁇ -D-glucosaminidase
• Serum creatinine concentrations were also measured.
• the renal artery and outflow vein were catheterised and the resulting preparation was placed in a chamber containing a Krebs solution heated to 37 °C.
• the oxygenised Krebs solution was pumped into the system by means of a pulsatile pump at a rate of 0.8 ml/min/g.
• Lithium was administered via the perfusion pump at a dose of 6 mEq/L after perfusion during the previous 20 minutes of a solution containing acetyl L-carnitine or propionyl L-carnitine (200 mM/L) or a combination of the two compounds.
• the venous perfusion fluid was collected at five-minute intervals for fifteen minutes and its histamine content was measured with a fluorometric method (Hakanson R., Anal. Biochem., 47, 356, 1972). Histamine release is considered a marker of the severity of tubular damage (Bertelli A., Drugs Exptl. Clin. Res., 7, 53, 1981).
• compositions according to the invention are given hereinbelow.
• pharmacologically acceptable salt of L-carnitine or alkanoyl L-carnitine is any salt of these with an acid that does not give rise to unwanted toxic or side effects.
• acids are well known to pharmacologists and to experts in pharmaceutical technology.
• acids examples include chloride; bromide; iodide; aspartate, acid, aspartate; citrate, acid citrate; tartrate; phosphate, acid phosphate; fumarate, acid fumarate; glycerol phosphate; glucose phosphate; lactate; maleate, acid maleate; orotate; oxalate, acid oxalate; sulphate, acid sulphate; trichloroacetate; trifluoroacetate and methane sulphonate.
• compositions of the invention can be formulated as tablets, lozenges, pills, capsules, granulates, syrups, vials or drops.

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• Health & Medical Sciences (AREA)
• Veterinary Medicine (AREA)
• Animal Behavior & Ethology (AREA)
• Pharmacology & Pharmacy (AREA)
• Chemical & Material Sciences (AREA)
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• Medicinal Chemistry (AREA)
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• Life Sciences & Earth Sciences (AREA)
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• General Chemical & Material Sciences (AREA)
• Urology & Nephrology (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Engineering & Computer Science (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Organic Chemistry (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Medicines Containing Plant Substances (AREA)

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• 1999
  • 1999-07-28 IT IT1999RM000483A patent/IT1306179B1/it active
• 2000
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